Chronic Elevation of RBCs Without Consistent Hb/Hct Elevation
The most critical first step is to determine whether this represents true polycythemia vera (PV) versus secondary erythrocytosis, by measuring serum erythropoietin (EPO) level and evaluating for JAK2 mutation, as inconsistent hemoglobin/hematocrit elevations do not exclude PV and may reflect concurrent iron deficiency, bleeding, or comorbid conditions that mask the full expression of the disease. 1
Initial Diagnostic Algorithm
Step 1: Confirm True Polycythemia and Assess Clinical Context
- Measure serum EPO level immediately as the pivotal discriminating test—low EPO (sensitivity ~70%, specificity >90%) strongly suggests PV, while elevated EPO points toward secondary causes 1
- Document whether hemoglobin/hematocrit ever exceeded the 95th percentile for sex and race (Hb >13 g/dL males, >12 g/dL females), or if there is a documented rise above the patient's individual baseline regardless of absolute values 1
- Evaluate for PV-related features that may accompany borderline-high hematocrit: thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly, aquagenic pruritus, unusual thrombosis (Budd-Chiari syndrome), or erythromelalgia 1
Critical pitfall: A normal-range hemoglobin/hematocrit does NOT exclude PV—the pathologic red cell mass may be masked by concurrent iron deficiency, occult bleeding, or comorbid conditions causing hypoxia (e.g., PV coexisting with chronic lung disease) 1. This explains your patient's inconsistent Hb/Hct pattern.
Step 2: Rule Out Secondary Causes Before Pursuing PV Workup
- Obtain thorough drug exposure history and review peripheral blood smear carefully 1
- Assess for hypoxia-driven erythrocytosis: chronic lung disease, sleep apnea, smoking history, cardiovascular disease with right-to-left shunt 1, 2
- Evaluate for inappropriate EPO production: renal pathology (cysts, tumors, post-transplant erythrocytosis), hepatocellular carcinoma, uterine fibroids 1
- Check iron studies, folate, B12, and assess for occult blood loss as these commonly confound the hematologic picture 1
Step 3: Pursue PV Diagnosis When EPO is Low or Borderline
If serum EPO is low (<normal range):
- Order JAK2 V617F mutation testing—present in ~98% of PV cases and confirms clonal myeloproliferation 3, 4
- Obtain bone marrow biopsy showing hypercellularity of all three cell lines with absent iron stores, which is highly characteristic 1, 5
- Note that PV can rarely present with elevated EPO (documented case reports exist), so if clinical suspicion remains high with other PV features, proceed with JAK2 testing regardless 6
If serum EPO is normal or elevated:
- PV becomes less likely but is not excluded—sensitivity of low EPO for PV is only ~70% 1
- Pursue bone marrow biopsy if PV-related features are present (splenomegaly, thrombocytosis, leukocytosis, microcytosis) despite normal/high EPO 1
- Consider congenital polycythemia with EPOR activating mutations if JAK2 is negative 1
Specific Hematologic Patterns to Recognize
PV patients characteristically exhibit:
- Leukocytosis and thrombocytosis in addition to erythrocytosis 4
- Hypochromic microcytic RBCs due to iron deficiency from chronic phlebotomy effect or occult bleeding 4
- Elevated leukocyte alkaline phosphatase and vitamin B12 levels (though these lack sensitivity/specificity) 1
This distinct CBC pattern should lower your threshold for PV workup even when Hb/Hct are inconsistently elevated 4.
Management Based on Diagnosis
If PV is Confirmed (JAK2+ with supportive findings):
Risk stratification determines treatment intensity:
- Low-risk PV (age <60, no thrombosis history): Phlebotomy to target hematocrit <45% plus low-dose aspirin 81mg daily 3
- High-risk PV (age ≥60 or prior thrombosis): Add cytoreductive therapy with hydroxyurea as first-line agent 7, 3
- Monitor for myelosuppression with baseline and ongoing CBC monitoring when using hydroxyurea 7
- Address modifiable thrombotic risk factors: smoking cessation, cardiometabolic disease control 3
Hydroxyurea dosing considerations:
- Individualize based on blood counts and response 7
- Reduce dose by 50% if creatinine clearance <60 mL/min 7
- Monitor for hemolytic anemia—if hemolysis persists, discontinue hydroxyurea 7
If Secondary Erythrocytosis is Confirmed:
- Treat the underlying condition (CPAP for sleep apnea, smoking cessation, optimize cardiopulmonary disease) 1, 2
- Phlebotomy may be considered if hematocrit remains dangerously elevated (>60%) despite treating secondary causes 1
- Do not use cytoreductive therapy as this is not clonal disease 2
Key Clinical Pitfalls to Avoid
Do not dismiss PV based solely on inconsistent Hb/Hct elevations—iron deficiency and comorbid conditions frequently mask the full hematologic picture 1
Do not order red cell mass (RCM) measurement routinely—it is costly, rarely changes management, and misses PV patients at the left tail of the RCM distribution 1
Do not rely on splenomegaly, leukocytosis, or thrombocytosis alone as diagnostic criteria—these lack sensitivity and specificity 1
Do not assume elevated EPO excludes PV—rare cases exist, and if clinical suspicion is high with other PV features, proceed with JAK2 testing 6
In patients with cardiovascular or lung disease comorbidities, recognize that PV can coexist with secondary causes of hypoxia, creating a mixed picture 1
Monitoring and Follow-up
- Repeat CBC in 3 months if initial workup is unrevealing and no PV-related features are present 1
- For confirmed PV on phlebotomy: Monitor hematocrit before each phlebotomy session, maintain <45% target 3
- For PV on cytoreductive therapy: Monitor CBC at baseline and throughout treatment for myelosuppression 7
- Long-term surveillance for thrombotic events, conversion to myelofibrosis (10-50% of patients), and acute leukemia (higher risk with myelosuppressive therapy) 5, 3